bms345541 and Inflammation

Topics: Apoptosis; Cartilage; Cells, Cultured; Chondrocytes; Curcuma; Curcumin; Cyclooxygenase 2; Humans; I-kappa B Kinase; Imidazoles; Inflammation; Interleukin-1beta; NF-kappa B; Osteoarthritis; Primary Cell Culture; Quinoxalines; Signal Transduction; SOX9 Transcription Factor; Tumor Necrosis Factor-alpha

The present study aimed to investigate the possible effects and regulatory mechanism of the inhibitor of nuclear factor‑κB kinase complex β subunit (IKKβ) inhibitor BMS‑345541 on airway inflammation, airway remodeling and epithelial‑mesenchymal transition (EMT) in an ovalbumin (OVA) exposure asthma model in mice. The asthma mouse model was generated by sensitization and challenge with OVA. BMS‑345541/dimethyl sulfoxide (DMSO) was administered perorally dairy in two therapeutic groups throughout the entire OVA challenge process. At 24 h following the last challenge, airway hyperresponsiveness (AHR) and airway inflammation were examined, and serum, bronchoalveolar lavage fluid (BALF) and lung samples were collected. Lung tissue was stained and assessed for pathological changes. The total number and classification of inflammatory cells in the BALF were examined. Levels of transforming growth factor β1 (TGFβ1) in the serum and BALF were measured using an enzyme‑linked immunosorbent assay. The differential expression of EMT regulators E‑cadherin and vimentin was detected by immunohistochemical staining, reverse transcription‑quantitative polymerase chain reaction analysis and western blot analysis. The results showed that OVA successfully induced allergic asthma. The asthmatic mice had AHR, airway inflammation, airway remodeling, a high expression of TGFβ1, and evidence of EMT. Following BMS‑345541 treatment, there was significant inhibition of pathophysiological signs, including increased pulmonary eosinophilia infiltration, mucus hypersecretion and AHR. Treatment with BMS‑345541 significantly reduced levels of TGFβ1. In addition, BMS‑345541 notably downregulated the expression of vimentin and increased the expression of E‑cadherin. These data suggested that the increased secretion of TGFβ1 induced by asthmatic inflammation can lead to EMT, and the IKKβ inhibitor BMS‑345541 may alter airway remodeling by preventing EMT in an OVA asthma model. Therefore, IKKβ inhibitors require investigation as potential asthma therapies.

Topics: Airway Remodeling; Animals; Asthma; Epithelial-Mesenchymal Transition; Female; Imidazoles; Inflammation; Mice; Mice, Inbred BALB C; Quinoxalines

Insulin-resistant states are commonly associated with chronic inflammation and hepatic overproduction of apolipoprotein B100 (apoB100), leading to hypertriglyceridemia and a metabolic dyslipidemic profile. Molecular mechanisms linking hepatic inflammatory cascades and the pathways of apoB100-lipoprotein production are, however, unknown. In the present study, we employed a diet-induced, insulin-resistant hamster model, as well as cell culture studies, to investigate the potential link between activation of hepatic inflammatory nuclear factor-kappaB (NF-kappaB) signaling cascade and the synthesis and secretion of apoB100-containing lipoproteins. Using an established insulin-resistant animal model, the fructose-fed hamster, we found that feeding fructose (previously shown to induce hepatic inflammation) for as little as 4 days reduced hepatic IkappaB (inhibitor of NF-kappaB) level, indicating activation of the inflammatory NF-kappaB cascade. Importantly, IKK (IkappaB kinase) inhibition was found to suppress apoB100 overproduction in fructose-fed hamster hepatocytes. As IKK, the upstream activator of NF-kappaB has been shown to inhibit insulin signaling, and insulin is a major regulator of apoB100, we modulated IKK activity in primary hamster hepatocytes and HepG2 cells and assessed the effects on hepatic apoB100 biosynthesis. Inhibition of the IKK-NF-kappaB pathway by BMS345541 and activation of the pathway by adenoviral-mediated IKK overexpression decreased and increased newly synthesized apoB100 levels, respectively. Pulse-chase and metabolic labeling experiments revealed that IKK activation regulates apoB100 levels at the levels of apoB100 biosynthesis and protein stability. Inhibition of the IKK-NF-kappaB pathway significantly enhanced proteasomal degradation of hepatic apoB100, while direct IKK activation led to reduced degradation and increased apoB100 mRNA translation. Together, our results reveal important links between modulation of the inflammatory IKK-NF-kappaB signaling cascade and hepatic synthesis and secretion of apoB100-containing lipoproteins. Hepatic inflammation may be an important underlying factor in hepatic apoB100 overproduction observed in insulin resistance.

Topics: Administration, Oral; Animals; Apolipoprotein B-100; Cell Line, Tumor; Cell-Free System; Cricetinae; Cysteine Proteinase Inhibitors; Extracellular Signal-Regulated MAP Kinases; Fructose; Gene Expression; Hepatocytes; Humans; I-kappa B Kinase; I-kappa B Proteins; Imidazoles; Inflammation; Leupeptins; Lipid Metabolism; Lipoproteins; Lipoproteins, VLDL; Liver; Male; Mesocricetus; NF-kappa B; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Protein Biosynthesis; Protein Kinase Inhibitors; Quinoxalines; Transfection; Tumor Necrosis Factor-alpha

Activation of innate immunity in the lungs can lead to a self-limited inflammatory response or progress to severe lung injury. We investigated whether specific parameters of NF-kappaB pathway activation determine the outcome of acute lung inflammation using a novel line of transgenic reporter mice. Following a single i.p. injection of Escherichia coli LPS, transient NF-kappaB activation was identified in a variety of lung cell types, and neutrophilic inflammation resolved without substantial tissue injury. However, administration of LPS over 24 h by osmotic pump (LPS pump) implanted into the peritoneum resulted in sustained, widespread NF-kappaB activation and neutrophilic inflammation that culminated in lung injury at 48 h. To determine whether intervention in the NF-kappaB pathway could prevent progression to lung injury in the LPS pump model, we administered a specific IkappaB kinase inhibitor (BMS-345541) to down-regulate NF-kappaB activation following the onset of inflammation. Treatment with BMS-345541 beginning at 20 h after osmotic pump implantation reduced lung NF-kappaB activation, concentration of KC and MIP-2 in lung lavage, neutrophil influx, and lung edema measured at 48 h. Therefore, sustained NF-kappaB activation correlates with severity of lung injury, and interdiction in the NF-kappaB pathway is beneficial even after the onset of lung inflammation.

Topics: Animals; Female; I-kappa B Kinase; Imidazoles; Immunity, Innate; Inflammation; Lipopolysaccharides; Lung; Lung Injury; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; NF-kappa B; Protein Kinase Inhibitors; Quinoxalines